3 years ago

Selectivity determinants of GPCR–G-protein binding

Selectivity determinants of GPCR–G-protein binding
Nadia Lund, M. Madan Babu, David E. Gloriam, Tilman Flock, Santhanam Balaji, Alexander S. Hauser
The selective coupling of G-protein-coupled receptors (GPCRs) to specific G proteins is critical to trigger the appropriate physiological response. However, the determinants of selective binding have remained elusive. Here we reveal the existence of a selectivity barcode (that is, patterns of amino acids) on each of the 16 human G proteins that is recognized by distinct regions on the approximately 800 human receptors. Although universally conserved positions in the barcode allow the receptors to bind and activate G proteins in a similar manner, different receptors recognize the unique positions of the G-protein barcode through distinct residues, like multiple keys (receptors) opening the same lock (G protein) using non-identical cuts. Considering the evolutionary history of GPCRs allows the identification of these selectivity-determining residues. These findings lay the foundation for understanding the molecular basis of coupling selectivity within individual receptors and G proteins.

Publisher URL: http://dx.doi.org/10.1038/nature22070

DOI: 10.1038/nature22070

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